1. Field of the Invention
This invention relates to a novel processed starch useful as a disintegrant to be incorporated in medicines, and also to a process for preparing such processed starch. It relates to the application of the processed starch as a disintegrant in medicines.
The processed starch according to the present invention is characterized as exhibiting appropriate water-absorbing and swelling properties, which are imparted thereto by physical treatments alone without any chemical modification. When the processed starch of the present invention is applied to the manufacture of solid pharmaceutical preparations such as tablets, granules, fine granules, pills and capsules, irrespectively of whether a dry method, a wet method or a semi-dry method is adopted, a rapid disintegrating property is given to these pharmaceutical preparations and a substantial bulking effect can be obtained. The processed starch of the present invention is further characterized in that when it is used for the manufacture of tablets, not only an effect of shortening the disintegration time of the tablets but also an effect of improving the disintegration pattern of the tablets to produce a good dissolution state of the active ingredient is also obtained.
2. Description of the Prior Art
As typical instances of disintegrants conventionally used for pharmaceutical preparations, there can be mentioned cellulose derivatives such as calcium carboxymethyl cellulose, low-viscosity sodium carboxymethyl cellulose, hydroxypropyl cellulose having a low degree of substitution and crosslinked sodium carboxymethyl cellulose; vegetable gums such as guar gum and sodium alginate; crosslinked polyvinyl pyrrolidone; cation exchange resins, and starch derivatives such as hydroxypropyl starch and carboxymethyl starch. Most of these disintegrants are chemical products, and even disintegrants derived from natural products such as cellulose and starch are obtained through chemical modification. Starch and cellulose which have not been subjected to a modification treatment with a chemical but show a good disintegrating activity have heretofore not been found. For example, cellulose per se has a moldability and is used as a binder in the field of medicines, but it is poor in its disintegrating activity.
As a cheap disintegrant which has not undergone chemical modification, there can be mentioned green starch, but since green starch is poor in the swelling property, in order to impart a rapid disintegrating property to a molded product, it is necessary to use green starch in large quantities, with the result that as is well-known, such defects as occurrence of the capping phenomenon and softening of the molded product with the lapse of time arise.
.alpha.-starch which is rendered completely soluble in cold water by a heat treatment or acid treatment of green starch is sometimes used as a disintegrant. However, when .alpha.-starch is used as a disintegrant, while an aqueous disintegrating medium such as water penetrates into fine pores of the molded product, .alpha.-starch is dissolved in the disintegrating liquid to drastically increase the viscosity of the disintegrating medium, with the result that smooth penetration of the disintegrating liquid is inhibited and a rapid disintegrating property can hardly be imparted to the molded product.
Another starch selected from natural starches which are abundant resources is used as a disintegrating agent. For example, U.S. Pat. No. 3,622,677 proposes a starch valuable as a binder-disintegrant, which consists of a mixture of birefringent granules and non-birefringent fragments, in which some aggregates of granules and fragments are present, the cold water solubility is about 4 to about 40% by weight, the swelling power of the dry product is about 2.5 to about 12, the bulk density is about 0.5 to about 0.7 g/ml, the moisture content is about 9 to about 16% based on the total weight, and the particle size may be substantially larger than 40 mesh but the particle size distribution is such that at least 90%, based on the total weight, of the powder has a size of more than 80 mesh, about 10 to about 70% of the powder has a particle size of more than 270 mesh and about 30 to about 90% of the powder has a particle size of less than 270 mesh. This starch is obtained by making compact a starting starch having a water content of about 20 to about 50% by weight at a temperature of 20.degree. to 50.degree. C. by a differential roll mill or parallel roll mill, and then drying and pulverizing the so treated starch. The starch obtained according to this method, however, is defective in that when a molded product is prepared according to the so-called wet granulation method where granulation is carried out after addition of water and the granulation product is compressed, no substantial disintegrating activity is attained. Furthermore, as disclosed in the above U.S. Patent, in order for the starch to exert a sufficient activity as a binder when it is incorporated into a tablet as a pharmaceutical molded product, various requirements should be satisfied. For example, the starch should be present in an amount of at least 50% based on the total weight of the tablet, and this starch should preferably be a sole binder to be added to the pharmaceutical composition. If these requirements are not satisfied, no satisfactory binding and disintegrating actions can be attained, and the freedom of selection of the recipe for a molded product is considerably restricted.
Furthermore, Japanese patent publication No. 5725/78 proposes a process for preparing granules and tablets by using .alpha.-starch having an .alpha.-type surface as a binder and a disintegrant. The starch described in this Japanese Patent Publication is a starch which has a surface modified to the .alpha.-type but retains the .beta.-type structure in the interior, which is prepared by a method comprising coating the surface of .beta.-starch, that is, green starch, with .alpha.-starch, a method comprising jetting high pressure steam to green starch fluidized in a fluidized layer or a method comprising suspending green starch in water and spraying the suspension in an air atmosphere having a temperature of 200.degree. to 400.degree. C. Since the surface of the obtained starch has a .alpha.-type structure, the starch has a good binding property, but a long time is required for an disintegrating medium to pass through the .alpha.-type portion and arrive at the .beta.-type portion, or while the disintegrating liquid penetrates into fine pores of the molded product, the .alpha.-type portion is dissolved in the disintegrating medium to increase the viscosity thereof. Accordingly, since penetration of the disintegrating medium is thus blocked and the disintegrating action is not satisfactory. As taught in "Handbook of Starch Chemistry," page 35, compiled by Jiro Nikuni and published by Asakura Shoten in 1977, .alpha.-starch has ordinarily high reactivity with enzymes and chemicals. Accordingly, if starch having a surface modified to the .alpha.-type is incorporated into medicines, the application is restricted because of such high reactivity.
It is known that a starch is heat-treated and the heat-treated starch is used as a food additive. For example, Japanese Laid-Open Patent Application No. 28691/80 (claiming the Convention priority based on British Patent Application No. 31695/78) discloses a technique of heating a root starch or tuber starch such as potato starch, tapioca starch or aloe root in the presence of 18 to 25% of water at a temperature of about 90.degree. to about 120.degree. C. to form a retarding type thickener and utilizing the thickener for preparation of sauces, gravy sauces or white sauces. As disclosed in this Japanese Laid-Open Patent Application, a most practical and industrial process for the preparation of starch having a retarding thickening function is one in which starch is merely heated in a closed heating apparatus at an ordinary water content (not in the state of an aqueous slurry) and a hydrothermal treatment is advanced to a desirable degree.
As shown in Comparative Examples given hereinafter, the so-obtained thickener has a small expanded volume but a high content of a cold water-soluble component, and it has the same defects as described above with respect to the product disclosed in Japanese Patent Publication No. 21471/79, which is the equivalent of U.S. Pat. No. 3,622,677. Thus, the thickener cannot be a disintegrant as intended in the present invention.